Pyrazolylquinazolinones as potassium channel openers

ABSTRACT

The present invention is directed to novel pyrazolylquinazolinone derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders related to potassium channel.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/774,696, filed on Feb. 17, 2006, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel pyrazolylquinazolinonederivatives, pharmaceutical compositions containing them and their usein the treatment of potassium channel related disorders. The compoundsof the invention are thus useful for treatment of various disorders.These include but are not limited to urinary incontinence, overactivebladder, hypertension, erectile dysfunction, female sexual disorders,dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy,stroke, Alzheimer's and Parkinson's diseases, myocardial injury andcoronary artery disease, as well as hair loss and baldness.

BACKGROUND OF THE INVENTION

Ion channels play a fundamental role in the hormeostasis of cellfunction through the regulation of the transmembrane movement of ions.Cellular activity can be affected by modifications of the activities ofthe ion channels. This leads to changes in membrane potentialdifference. Potassium channels are a diverse and ubiquitous group of ionchannels. They principally regulate the resting membrane potential ofthe cell and attenuate the level of excitation of cells. A functionalKATP channel is a hetero-octamer assembled from four inward rectifyingpotassium channel subunits (Kir6.2) and four sulfonylurea receptor (SUR)subunits. There are two SUR genes, SUR1 and SUR2. SUR1/Kir6.2 channelsare found in the pancreas and brain. Two major splice variants arisefrom the SUR2 gene, SUR2A and SUR2B, that differ only at the C-terminal42 amino acids. SUR2A/Kir6.2 channels are found in cardiac and skeletaltissues whereas SUR2B/Kir6.2 channels are found in smooth muscles ofmany tissues including bladder (Aguilar-Bryan, 1998). A number ofdiseases or conditions may be treated with potassium channel openers.This includes overactive bladder, urinary incontinence, male erectiledysfunction, female sexual disorders, premature labor, benign prostatehyperplasia (BPH), dysmenorrhea, neurodegeneration, stroke, pain,coronary artery disease, angina, ischemia, eating disorders, irritablebowl syndrome and alopecia.

Urinary incontinence (UI) is a disease that can affect the overallquality of life of a patient. Overactive bladder (OAB) is the mostprevalent form of UI, with reported prevalence rate from 40 to 70% ofall diagnosed UI cases (Wein, 2000). OAB is characterized by thesymptoms of increased urinary frequency, urgency, and involuntary lossof urine. A primary cause of OAB is an oversensitive bladder thatcontracts unexpectedly and involuntarily. The ideal pharmaceutical agentshould suppress the involuntary contraction while leaving the normalvoiding contractions intact. ATP-sensitive potassium channel openers(KCO) could serve as such agents. The ATP-sensitive potassium channels(KATP) are expressed in bladder smooth muscle and function as keyregulators of the resting membrane potential in these cells. Compoundsthat selectively open these channels hyperpolarize the cell and decreasecellular excitability, resulting in suppression of involuntary bladdercontractions, while leaving the normal micturition circuitry intact.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula I:

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, carboxy,C₁₋₄ alkyl, halogenated C₁₋₄alkyl, —C(O)—C₁₋₄ alkyl, —C(O)-(halogenatedC₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, CN and NO₂;

R² is selected from the group consisting of hydrogen, halogen, carboxy,C₁₋₄ alkyl, halogenated C₁₋₄alkyl, —C(O)—C₁₋₄ alkyl, —C(O)-(halogenatedC₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, CN and NO₂;

R³ is selected from the group consisting of hydrogen, C₁₋₄ alkyl andhalogenated C₁₋₄alkyl;

R⁴ is selected from the group consisting of hydrogen, carboxy, C₁₋₄alkyl, halogenated C₁₋₄alkyl, aryl, heteroaryl, —C(O)-alkyl,—C(O)-(halogenated C₁₋₄alkyl) and —C(O)O—C₁₋₄alkyl;

wherein the aryl or heteroaryl whether alone or as part of a substituentgroup is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁₋₄alkyl,C₁₋₄alkoxy, halogenated C₁₋₄alkyl, halogenated C₁₋₄alkoxy, cyano, nitro,—C(O)O—C₁₋₄alkyl and —S(O)₀₋₂—C₁₋₄alkyl;

or a pharmaceutically acceptable salt thereof.

It will be appreciated that the compounds of formula (I) can exists astautomers. Those skilled in the art will recognized that when N(1) andC(2) form a double bond, then C(2) and N(3) form a single bond. In theother tautomeric form when N(1) and C(2) form a single bond, then C(2)and N(3) form a double bond. In this latter tautomeric form, the H atomillustrated as bonded to N(3) will, of course, be bonded to N(1).

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating disorders related toion channels, preferably a potassium ion channel, more preferably anATP-sensitive potassium ion channel, comprising administering, to asubject in need thereof, a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above.

An example of the invention is a method for treating a disorder selectedfrom the group consisting of urinary incontinence, overactive bladder,hypertension, erectile dysfunction, female sexual disorders,dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy,stroke, Alzheimer's disease, Parkinson's disease, myocardial injury,coronary artery disease, hair loss and baldness, preferably urinaryincontinence, comprising administering, to a subject in need thereof, aneffective amount of any of the compounds or pharmaceutical compositionsdescribed above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)urinary incontinence, (b) overactive bladder, (c) hypertension, (d)erectile dysfunction, (e) female sexual disorders, (f) dysmenorrhea, (g)irritable bowl syndrome, (h) airway hyperactivity, (i) epilepsy, (j)stroke, (k) Alzheimer's disease, (l) Parkinson's disease, (m) myocardialinjury, (n) coronary artery disease, (o) hair loss or (p) baldness, in asubject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein R¹, R², R³ and R⁴ are as herein defined. The compounds of thepresent invention are potassium channels openers. The compounds of thepresent are thus useful for treatment of various disorders including,but not limited to, urinary incontinence, overactive bladder,hypertension, erectile dysfunction, female sexual disorders,dysmenorrhea, irritable bowl syndrome, airway hyperactivity, epilepsy,stroke, Alzheimer's and Parkinson's diseases, myocardial injury,coronary artery disease as well as hair loss and baldness. Preferably,the compounds of the present invention are useful in the treatment ofurinary incontinence or overactive bladder.

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine. Preferably, the halogen is chlorine, bromine or fluorine, morepreferably, chlorine or fluorine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Similarly, the term“C₁₋₄alkyl” whether used alone or as part of a substituent group,include straight and branched chains containing 4 carbon atoms. Forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and t-butyl.

As used herein, unless otherwise noted, “alkoxy” whether used alone oras part of a substituent group, shall denote an oxygen ether radical ofthe above described straight or branched chain alkyl groups. Forexample, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxyand the like. Similarly, the term “C₁₋₄alkoxy” whether used alone or aspart of a substituent group, shall denote an oxygen ether radical of theabove described straight or branched chain C₁₋₄alkyl groups. Forexample, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, and the like.

As used herein, unless otherwise noted, the term “halogen substitutedC₁₋₄alkyl” shall mean any C₁₋₄alkyl group as defined above substitutedwith at least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include but are not limited to —CF₃,—CHF₂, —CH₂—CF₃, —CF₂—CF₂—CF₂—CF₃, and the like. Similarly, as usedherein, unless otherwise noted, the term “halogen substitutedC₁₋₄alkoxy” shall mean any C₁₋₄alkoxy group as defined above substitutedwith at least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include but are not limited to —OCF₃,—OCHF₂, —OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like. Preferably, the aryl group is phenyl or naphthyl, morepreferably, phenyl.

As used herein, unless otherwise noted, the term “partially unsaturated”when referring to a ring structure shall mean that the ring structure isstable and contains at least one unsaturated bond (i.e. at least onedouble bond). Suitable examples include, but are not limited tocyclohexenyl, and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,and the like.

As used herein, unless otherwise noted, the term “heteocyclyI” shallmean any heteroaryl or heterocyclyl group, as defined above. Preferably,the heterocyclyl group comprises at least one nitrogen atom. Morepreferably, the heterocyclyl group comprises one to three heteroatomsindependently selected from the group consisting of O, S and N. Morepreferably still, the heterocyclyl group comprises one to twoheteroatoms independently selected from the group consisting of O, S andN. Preferably, the heterocyclyl group comprises one N atom and furthercomprises one additional heteroatom independently selected from thegroup consisting of O, S and N. Preferably, the heterocyclyl group issaturated, aromatic or partially aromatic, more preferably, theheterocyclyl group is aromatic or benzo-fused.

Preferably, the heterocyclyl is selected from the group consisting of4,5-dihydro-oxazolyl, piperidiny, imidazolyl, pyrimidinyl, pyrazolyl,pyrazolinyl, pyridazinyl, indolinyl, indazolyl, isoindolyl,pyrrolo[3,4-c]pyridinyl, benzimidazolyl, benzoisothiazolyl,benzoisoxazolyl, benzthiazolyl, benzoxazolyl, quinazolinyl, quinolinyland isoquinolinyl.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., aryl, heterocycloalkyl,heteroaryl), that group may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl-C₁₋₄alkyl-amino-carbonyl-C₁₋₄alkyl-”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows: p DCM=Dichloromethane

DMAC=Dimethylacetamide

DMF=N,N-Dimethylformamide

DMSO=Dimethylsulfoxide

Et=Ethyl (i.e —CH₂CH₃)

Etl=Ethyl Iodine

EtOAc=Ethyl acetate

HPLC=High Pressure Liquid Chromatography

KO-t-Bu or t-Bu-OK=Potassium t-butoxide

Me=Methyl (i.e. —CH₃)

Mel=Methyl Iodide

MeOH=Methanol

NaOAc=Sodium Acetate

TEA or Et₃N=Triethylamine

THF=Tetrahydrofuran

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The present invention includes within its scope “prodrugs” of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The present invention includes within its scope “pharmaceuticallyacceptable salts” of the compounds of this invention. For use inmedicine, the salts of the compounds of this invention refer tonon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of compounds according to this invention orof their pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds include acid addition salts which may,for example, be formed by mixing a solution of the compound with asolution of a pharmaceutically acceptable acid such as hydrochloricacid, sulfuric acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g., sodium or potassium salts; alkalineearth metal salts, e.g., calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g., quaternary ammonium salts. Thus,representative pharmaceutically acceptable salts include the following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, CNand NO₂. In another embodiment of the present invention, R¹ is selectedfrom the group consisting of hydrogen, halogen, halogenated C₁₋₄alkyland cyano. In another embodiment of the present invention, R¹ isselected from the group consisting of hydrogen, bromo, chloro and cyano.In another embodiment of the present invention, R¹ is bromo and chloro.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, CNand NO₂. In another embodiment of the present invention, R² is selectedfrom the group consisting of hydrogen, halogen and halogenatedC₁₋₄alkyl. In another embodiment of the present invention, R² isselected from the group consisting of hydrogen and halogenatedC₁₋₄alkyl. In another embodiment of the present invention, R² isselected from the group consisting of hydrogen and trifluoromethyl.

In an embodiment of the present invention, R³ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl and halogenated C₁₋₄alkyl. In anotherembodiment of the present invention, R³ is C₁₋₄alkyl. In anotherembodiment of the present invention, R³ is methyl.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of hydrogen, carboxy, C₁₋₄ alkyl, halogenated C₁₋₄alkyl,phenyl and —C(O)O—C₁₋₄alkyl. In another embodiment of the presentinvention, R⁴ is hydrogen, C₁₋₄alkyl and C(O)O—C₁₋₄alkyl. In anotherembodiment of the present invention, R³ is hydrogen and C(O)O-Et.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, R², R³ and n) are independently selected to be anyindividual substituent or any subset of substituents selected from thecomplete list as defined herein.

Representative compounds of the present invention are as listed inTables 1 below.

TABLE 1 Compounds of Formula (I) ID R¹ R² R³ R⁴ 1 Cl H Me H 2 Br H Me H3 H CF₃ Me H 4 Cl H Me C(O)—O—Et

Synthesis

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (II), a knowncompound or compound prepared by known methods is reacted with asuitably substituted (III), known compounds, in the presence of a basesuch as TEA, DIPEA, and the like, in an organic solvent such DCM, THF,and the like, preferably at a temperature in the range of from about 0°C. and room temperature, more preferably at a temperature of 0° C., toyield the corresponding compound of formula (IX).

The compound of formula (IX) is treated with a base, such as ammoniahydroxide, sodium hydride, and the like, in an organic solvent such asethanol, methanol, THF, and the like, at a temperature in the range offrom about 50° C. and about 80° C., to yield the corresponding compoundsof formula (X).

The compound of formula (X) is treated with a diazo source R₄CHN₂, aknown compound or compound prepared by known methods, such as TMSdiazomethane, diazo ethyl acetate and the like, in an organic solventsuch as ether, THF, dioxane and the like, at a temperature in the rangeof from about 50° C. and 80° C., to yield the corresponding compounds offormula (I).

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie,Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groupsin Organic Synthesis, John Wiley & Sons, 1991. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore of the compounds of the present invention selected as the activeingredient is intimately admixed with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 50-100 mg and maybe given at a dosage of from about 0.5-5.0 mg/kg/day, preferably fromabout 1.0-3.0 mg/kg/day. The dosages, however, may be varied dependingupon the requirement of the patients, the severity of the conditionbeing treated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders related to ion channels, for examplepotassium ion channels, described in the present invention may also becarried out using a pharmaceutical composition comprising any of thecompounds as defined herein and a pharmaceutically acceptable carrier.The pharmaceutical composition may contain between about 0.01 mg and1000 mg, preferably about 1 to 500 mg, more preferably, 10 to 100 mg ofthe compound, and may be constituted into any form suitable for the modeof administration selected. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixers, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders related to ion channels, for examplepotassium ion channels, is required.

The daily dosage of the products may be varied over a wide range from0.01 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250, 500 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.01 mg/kg to about 300 mg/kg of body weight per day.Preferably, the range is from about 0.5 to about 5.0 mg/kg of bodyweight per day, most preferably, from about 1.0 to about 3.0 mg/kg ofbody weight per day. The compounds may be administered on a regimen of 1to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

EXAMPLE 1 5-Chloro-2-(2-methyl-acryloylamino)-benzamide

2-Amino-5-chloro-benzamide (2.5 mmoL), a literature known compound, wastreated with TEA (3.0 mmoL) followed by methylacryl chloride (2.5 mmoL)in DCM at 0° C. The reaction was slowly warmed to room temperature andkept for another 2 h. The reaction mixture was then partitioned betweenDCM and water. The organic layer was washed with sat. Na₂CO₃, brine,dried over anhydrous Na₂SO₄, filtered, concentrated and purified bysilica gel column chromatography to afford the title compound as a whitesolid.

¹H NMR: (CDCl₃) δ 8.70 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J=7.5Hz, 1H), 6.60 (br, s, 2H), 6.05 (br, s, 1H), 6.00 (s, 1H), 5.51 (s, 1H),2.05 (s, 3H). MS (m/z): MH⁺239.

EXAMPLE 2 5-Bromo-2-(2-methyl-acryloylamino)-benzamide

Following the procedure described in the Example 1, using2-amino-5-chloro-benzamide as starting material to yield the titlecompound as a white solid.

¹H NMR: (CDCl₃) δ 8.65 (d, J=7.5 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J=7.5Hz, 1H), 6.40 (br, s, 2H), 6.00 (s, 1H), 5.91 (br, s, 1H), 5.55 (s, 1H),2.10 (s, 3H).

MS (m/z): MH⁺284.

EXAMPLE 3 2-(2-Methyl-acryloylamino)-4-trifluoromethyl-benzamide

Following the procedure described in the Example 1, using2-amino-4-trifluoromethyl-benzamide as starting material to yield thetitle compound as a white solid.

¹H NMR: (CDCl₃) δ 9.05 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.5Hz, 1H), 6.50 (br, s, 1H), 6.00 (s, 1H), 5.91 (br, s, 1H), 5.55 (s, 1H),2.10 (s, 3H).

MS (m/z): MH⁺273.

EXAMPLE 4 6-Chloro-2-isopropenyl-3H-quinazolin-4-one

5-Chloro-2-(2-methyl-acryloylamino)-benzamide (1.5 mmoL) in EtOH (10 mL)was treated with ammonia hydroxide (˜3.0 mmoL) at 80° C. for 4 h. Thereaction was then cooled down and the solvent was removed. The reactionmixture was then partitioned between DCM and water. The organic layerwas washed with sat. NH₄Cl, brine, dried over anhydrous Na₂SO₄,filtered, concentrated and purified by silica gel column chromatographyto afford the title compound as a white solid.

¹H NMR: (CDCl₃) δ 8.45 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.75 (br, s,1H), 7.30 (d, J=8.5 Hz, 1H), 5.85 (s, 1H), 5.55 (s, 1H), 2.05 (s, 3H).MS (m/z): MH⁺221.

EXAMPLE 5 6-Bromo-2-isopropenyl-3H-quinazolin-4-one

Following the procedure described in the Example 4, using5-bromo-2-(2-methyl-acryloylamino)-benzamide as starting material toyield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 10.50 (br, s, 1H), 8.40 (s, 1H), 7.85 (d, J=7.5 Hz,1H), 7.62 (d, J=7.5 Hz, 1H), 6.05 (s, 1H), 5.71 (s, 1H), 2.25 (s, 3H).MS (m/z):

MH⁺266.

EXAMPLE 6 2-Isopropenyl-7-trifluoromethyl-3H-quinazolin-4-one

Following the procedure described in the Example 4, using2-(2-Methyl-acryloylamino)-4-trifluoromethyl-benzamide as startingmaterial to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 7.56 (d, J=8.0 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.70(br, s, 1H), 6.10 (s, 1H), 5.71 (s, 1H), 2.25 (s, 3H). MS (m/z): MH⁺255.

EXAMPLE 76-Chloro-2-(3-methyl-3,4-dihydro-2H-pyrazol-3-vi)-3H-quinazolin-4-one

6-Chloro-2-isopropenyl-3H-quinazolin-4-one (1 mmoL) in THF (5 mL) wastreated with TMSCHN₂ (1.0 N, 3.0 mmoL) at 50° C. for 4 h. The solventwas removed and the residue was purified by silica gel columnchromatography to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 10.61 (br, s, 1H), 8.21 (s, 1H), 7.65 (d, J=6.5 Hz,1H), 7.60 (d, J=7.5 Hz, 1H), 6.81 (br, s, 1H), 3.15 (abq, J=12.5 Hz,2H), 1.70 (s, 3H). MS (m/z): MH⁺263.

EXAMPLE 86-Bromo-2-(3-methyl-3,4-dihydro-2H-pyrazol-3-vi)-3H-quinazolin-4-one

Following the procedure described in the Example 7, using6-bromo-2-isopropenyl-3H-quinazolin-4-one and TMSCHN₂ as startingmaterials to yield the title compound as a white solid.

¹H NMR: (CDCl₃) δ 8.01 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.62 (d, J=7.5Hz, 1H), 6.91 (br, s, 1H), 3.55 (abq, J=12.5 Hz, 1H), 2.60 (abq, J=12.5Hz, 1H), 1.55 (s, 3H). MS (m/z): MH⁺308.

EXAMPLE 92-(3-Methyl-3,4-dihydro-2H-pyrazol-3-yl)-7-trifluoromethyl-3H-quinazolin-4-one

Following the procedure in Example 7, using2-isopropenyl-7-trifluoromethyl-3H-quinazolin-4-one and TMSCHN₂ asstarting materials yielded the title compound as a white solid.

¹H NMR: (CDCl₃) δ 10.70 (br, s, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.95 (s,1H), 7.65 (d, J=7.5 Hz, 1H), 3.25 (abq, J=10.5 Hz, 1H), 1.75 (s, 3H). MS(m/z): MH⁺297.

EXAMPLE 105-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester

Following the procedure in Example 7, using6-Chloro-2-isopropenyl-3H-quinazolin-4-one and diazo ethyl acetate asstarting materials yielded the title compounds as a white solid.

¹H NMR: (CDCl₃) δ 8.25 (s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.55 (d, J=7.5Hz, 1H), 7.00 (s, 1H), 4.35 (q, J=9.5 Hz, 2H), 3.60 (abq, J=10.5 Hz,1H), 3.25 (abq, J=10.5 Hz, 1H), 1.75 (s, 3H), 1.40 (q, J=9.5 Hz, 3H). MS(m/z):

MH⁺335.

EXAMPLE 11 Potassium Channel Assay

TE671 human medulloblastoma cells were obtained from ATCC and grown inDulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetalbovine serum, 100 U/ml penicillin and 100 U/ml streptomycine.

The day before testing, the cells were plated in black 96-well plates at50K/well. On the day of testing, the growth media was removed, then 100μl of FLIPR buffer (20 mM HEPES, 120 mM NaCl, 2 mM KCl, 2 mM CaCl₂, 1 mMMgCl₂, 5 mM Glucose) and 100 μl of Membrane Potential Assay Dye(Molecular Devices) dissolved in FLIPR buffer were added to each well.The cells were incubated at room temperature for 15 to 30 min.

The effect of test compounds on KATP channels were evaluated on afluorometric imaging plate reader (FLIPR, Molecular Devices) at roomtemperature. After a baseline period, 50 μl of 5× stock solution of testcompound prepared in FLIPR buffer was added and fluorescent change wasmonitored for 3 minutes. After this reading, glyburide, a KATP channelblocker, was added to a final concentration of 5 μM to check thespecificity of the test compound as a KATP channel openers.Hyperpolarization resulting from KATP channel opening was observed as adecrease in fluorescent intensity.

Representative compounds of the present invention were tested accordingto the procedure described above, with results as listed in Table 2below. Test compound activity was determined as the percent. A compoundwas designated as active if it produced greater than or equal to 10%response at 30 μM. A compound was designated as inactive if it producedless than 10% response at 30 μM.

TABLE 2 ID No response 1 active 2 active 3 active 4 active

EXAMPLE 12

As a specific embodiment of an oral composition, 100 mg of the compoundprepared as in Example 7 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula I:

wherein: R¹ is selected from the group consisting of hydrogen, halogen,C₁₋₄ alkyl, halogenated C₁₋₄alkyl, CN and NO₂; R² is selected from thegroup consisting of hydrogen, halogen, C₁₋₄ alkyl, halogenatedC₁₋₄alkyl, CN and NO₂; R³ is C₁₋₄ alkyl; and R⁴ is selected from thegroup consisting of hydrogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, phenyland —C(O)O—C₁₋₄alkyl; or a pharmaceutically acceptable salt thereof. 2.A compound as in claim 1, wherein R¹ is selected from the groupconsisting of hydrogen, bromo, chloro and cyano; R² is selected from thegroup consisting of hydrogen and trifluoromethyl; R³ is methyl; and R⁴is hydrogen and C(O)—O-Et.
 3. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of claim
 1. 4. Aprocess for making a pharmaceutical composition comprising mixing acompound of claim 1 and a pharmaceutically acceptable carrier.
 5. Amethod of treating a disorder related to ion channels, wherein thedisorder is selected from the group consisting of hypertension,myocardial injury, coronary artery disease and stroke, comprisingadministering, to a subject in need thereof, a therapeutically effectiveamount of the compound of claim 1.